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Protein Cell. 2018 Apr;9(4):333-350. doi: 10.1007/s13238-018-0517-8. Epub 2018 Feb 23.

Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome.

Wu Z1,2,3, Zhang W2,3,4, Song M3,5, Wang W2,3, Wei G6, Li W4, Lei J4, Huang Y7, Sang Y8, Chan P4, Chen C2,3, Qu J9,10, Suzuki K11,12, Belmonte JCI13, Liu GH14,15,16,17.

Author information

1
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
2
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
3
University of Chinese Academy of Sciences, Beijing, 100049, China.
4
National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China.
5
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
6
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
7
Department of Medical genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
8
Department of Pediatric Endocrinology and Genetic Metabolism, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
9
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. qujing@ioz.ac.cn.
10
University of Chinese Academy of Sciences, Beijing, 100049, China. qujing@ioz.ac.cn.
11
Institute for Advanced Co-Creation Studies, Osaka University, Osaka, 560-8531, Japan. ksuzuki@chem.es.osaka-u.ac.jp.
12
Graduate School of Engineering Science, Osaka University, Osaka, 560-8531, Japan. ksuzuki@chem.es.osaka-u.ac.jp.
13
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, 92037, USA. belmonte@salk.edu.
14
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. ghliu@ibp.ac.cn.
15
University of Chinese Academy of Sciences, Beijing, 100049, China. ghliu@ibp.ac.cn.
16
National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China. ghliu@ibp.ac.cn.
17
Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China. ghliu@ibp.ac.cn.

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.

KEYWORDS:

HGPS; WRN; Werner syndrome; aging; lamin; stem cell

PMID:
29476423
PMCID:
PMC5876188
DOI:
10.1007/s13238-018-0517-8
[Indexed for MEDLINE]
Free PMC Article

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